Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

and

This portion summarises what we have covered and is now familiar to the reader. There are three related topics, and an extension of this embraces other volumes and chapters before and after this reading. This approach to the document has advantages over the multiple authored textbooks that are and have been pervasive as a result of the traditional publication technology. It has been stated by the founder of ScoopIt, that amount of time involved is considerably less than required for the original publications used, but the organization and construction is a separate creative process. In these curations we amassed on average five articles in one curation, to which, two or three curators contributed their views. There were surprises, and there were unfulfilled answers along the way. The greatest problem that is being envisioned is the building a vision that bridges and unmasks the hidden “dark matter” between the now declared “OMICS”, to get a more real perspective on what is conjecture and what is actionable. This is in some respects unavoidable because the genome is an alphabet that is matched to the mino acid sequences of proteins, which themselves are three dimensional drivers of sequences of metabolic reactions that can be altered by the accumulation of substrates in critical placements, and in addition, the proteome has functional proteins whose activity is a regulatory function and not easily identified. In the end, we have to have a practical conception, recognizing the breadth of evolutionary change, and make sense of what we have, while searching for more.

We introduced the content as follows:

1. We introduce the concept of curation in the digital context, and it’s application to medicine and related scientific discovery.

Topics were chosen were used to illustrate this process in the form of a pattern, which is mostly curation, but is significantly creative, as it emerges in the context of this e-book.

Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy is handled all in one chapter.

PCI for valves vs Open heart Valve replacement

PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.

2. The etiology, or causes, of cardiovascular diseases consist of mechanistic explanations for dysfunction relating to the heart or vascular system. Every one of a long list of abnormalities has a path that explains the deviation from normal. With the completion of the analysis of the human genome, in principle all of the genetic basis for function and dysfunction are delineated. While all genes are identified, and the genes code for all the gene products that constitute body functions, there remains more unknown than known.

3. Human genome, and in combination with improved imaging methods, genomics offers great promise in changing the course of disease and aging.

4. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.

Curation

Curation is an active filtering of the web’s and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes.
Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view. Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blindmen of the Sufi tale. One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive. The same source says “Scoop.it is my content marketing testing “sandbox”. In sharing, he says that comments provide the framework for what and how content is shared.

Healthcare and Affordable Care Act

We enter year 2014 with the Affordable Care Act off to a slow start because of the implementation of the internet signup requiring a major repair, which is, unfortunately, as expected for such as complex job across the US, and with many states unwilling to participate. But several states – California, Connecticut, and Kentucky – had very effective state designed signups, separate from the federal system. There has been a very large rush and an extension to sign up. There are many features that we can take note of:

1. The healthcare system needed changes because we have the most costly system, are endowed with advanced technology, and we have inexcusable outcomes in several domains of care, including, infant mortality, and prenatal care – but not in cardiology.

2. These changes that are notable are:

The disparities in outcome are magnified by a large disparity in highest to lowest income bracket.

This is also reflected in educational status, and which plays out in childhood school lunches, and is also affected by larger class size and cutbacks in school programs.

This is not helped by a large paralysis in the two party political system and the three legs of government unable to deal with work and distraction.

Unemployment is high, and the banking and home construction, home buying, and rental are in realignment, but interest rates are problematic.

3. The medical care system is affected by the issues above, but the complexity is not to be discounted.

The medical schools are unable at this time to provide the influx of new physicians needed, so we depend on a major influx of physicians from other countries

The technology for laboratories, proteomic and genomic as well as applied medical research is rejuvenating the practice in cardiology more rapidly than any other field.

In fields that are imaging related the life cycle of instruments is shorter than the actual lifetime use of the instruments, which introduces a shortening of ROI.

Hospitals are consolidating into large consortia in order to maintain a more viable system for referral of specialty cases, and also is centralizing all terms of business related to billing.

There is reduction in independent physician practices that are being incorporated into the hospital enterprise with Part B billing under the Physician Organization – as in Partners in Greater Boston, with the exception of “concierge” medical practices.

There is consolidation of specialty laboratory services within state, with only the most specialized testing going out of state (Quest, LabCorp, etc.)

Medicaid is expanded substantially under the new ACA.

The federal government as provider of services is reducing the number of contractors for – medical devices, diabetes self-testing, etc.

The current rearrangements seeks to provide a balance between capital expenses and fixed labor costs that it can control, reduce variable costs (reagents, pharmaceutical), and to take in more patients with less delay and better performance – defined by outside agencies.

Cardiology, Genomics, and calcium ion signaling and ion-channels in cardiomyocyte function in health and disease – including heart failure, rhythm abnormalities, and the myoneural release of neurotransmitter at the vesicle junction.

Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

calcium and actin skeleton, signaling, cell motility

hypertension & vascular compliance

Genetics of Conduction Disease

Ca+ stimulated exostosis: calmodulin & PKC (neurotransmitter)

complications & MVR

disruption of Ca2+ homeostasis cardiac & vascular smooth muscle

synaptotagmin as Ca2+ sensor & vesicles

atherosclerosis & ion channels

It is increasingly clear that there are mutations that underlie many human diseases, and this is true of the cardiovascular system. The mutations are mistakes in the insertion of a purine nucleotide, which may or may not have any consequence. This is why the associations that are being discovered in research require careful validation, and even require demonstration in “models” before pursuing the design of pharmacological “target therapy”. The genomics in cardiovascular disease involves very serious congenital disorders that are asserted early in life, but the effects of and development of atherosclerosis involving large and medium size arteries has a slow progression and is not dominated by genomic expression. This is characterized by loss of arterial elasticity. In addition there is the development of heart failure, which involves the cardiomyocyte specifically. The emergence of regenerative medical interventions, based on pleuripotent inducible stem cell therapy is developing rapidly as an intervention in this sector.

Finally, it is incumbent on me to call attention to the huge contribution that research on calcium (Ca2+) signaling has made toward the understanding of cardiac contraction and to the maintenance of the heart rhythm. The heart is a syncytium, different than skeletal and smooth muscle, and the innervation is by the vagus nerve, which has terminal endings at vesicles which discharge at the myocyte junction. The heart specifically has calmodulin kinase CaMK II, and it has been established that calmodulin is involved in the calcium spark that triggers contraction. That is only part of the story. Ion transport occurs into or out of the cell, the latter termed exostosis. Exostosis involves CaMK II and pyruvate kinase (PKC), and they have independent roles. This also involves K+-Na+-ATPase. The cytoskeleton is also discussed, but the role of aquaporin in water transport appears elsewhere, as the transport of water between cells. When we consider the Gibbs-Donnan equilibrium, which precedes the current work by a century, we recall that there is an essential balance between extracellular Na+ + Ca2+ and the intracellular K+ + Mg2+, and this has been superceded by an incompletely defined relationship between ions that are cytoplasmic and those that are mitochondrial. The glass is half full!

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1. 2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival.

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

contribute to microvascular dysfunction [29, 60]. But

ion channels play a critical role in microvascular endothelial

and smooth muscle function.

Therefore, we hypothesized that alterations of coronary ion channels could be the primary cause in a chain of events leading to

microvascular dysfunction and

myocardial ischemia,

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

IHD and single-nucleotide polymorphisms (SNPs) for genes encoding several regulators involved in CBFR, including

ion channels acting in vascular smooth muscle and/or

endothelial cells of coronary arteries.

Discussion

Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

hypertension = 17 %,

T2DM = 34.1 %,

dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD

and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an

association of this SNP with CAD in Asian populations [74]. In addition,

this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].

Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

high-grade coronary stenosis or occlusion [19].

As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in bothcoronary artery smooth muscle cells and endothelial cells

Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.

K-ATP channel activation results in an outward flux of potassium and

consequent hyperpolarization, resulting in

voltage-gated calcium channel closure,

decreased Ca2+ influx, and ultimately

vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

may have originated in a common ancestor, further indicating a

possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

rs5215_GG against developing CAD and

a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).

The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening

are both impaired in diabetes mellitus [39].

It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,

independent of the presence of either diabetes mellitus or dyslipidemia.

These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,

regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

pergolide [25],

4-amino-pyridine [32], and

correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

cardiac metabolic demand and

coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

catalyzes the hydrolysis of ATP coupled with the

translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

genetic variants of SERCA and the

prevalence of microvascular dysfunction or IHD.

Conclusions

This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients

with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.

Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

Limitations and future perspectives

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.

2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.

3. There is a lack of ethnic diversity of our cohort.

4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.

5. There is a lack of functional characterization of the described genetic polymorphisms.

6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel). Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as

in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and

the same ethno-geographic Caucasian origin) and

Exclusion Criteria

previous allergic reaction to iodine contrast,

renal failure,

simultaneous genetic disease,

cardiogenic shock,

non- ischemic cardiomyopathy

All patients signed an informed consent document –

prior to participation in the study, which included

acknowledgement of the testing procedures to be performed
(i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated database.

Study Design

(a) Standard therapies were administered, according to current guidelines [36, 68].(b) An echocardiography was performed before and after coronary angiography
(c) Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler ﬂow wire to evaluate

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

related to ion channels and/or reported to be associated with

microvascular dysfunction and/or myocardial ischemia and/or

diseases correlated to IHD, such as diabetes mellitus.

Polymorphisms for the following genes were analyzed:

NOS3 (endothelial nitric oxide synthase, eNOS),

ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),

SCN5A (voltage-dependent Na+ channel,

Nav1.5),

KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),

KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and

KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as

the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and

four previously described variants [26, 47, 71, 72].

We also examined

the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the ﬁrst to compare

the prevalence of SNPs in genes encoding several effectors (including ion channels)

involved in CBFR between these groups of patients.

No deﬁnite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

The clinical motivations for coronary artery imaging include identifying and characterizing obstructive lesions, analyzing suitability for various feasible interventions, and assessing comparative risk with and without interventions. With improvements in non-invasive detection of fixed obstructions in the coronary arteries, it should not be surprising that half of the lesions that cause heart attacks (myocardial infarction) among those who had recent imaging consisted of unstable plaques that were less than 50% obstructive. Therefore there is growing interest not only in more reliable detection of lesions that exceed 50% obstruction, but also improved characterization of lesions that are not obstructive but may be unstable.

By way of analogy, think of impaired blood supply to the heart as a traffic jam in a roadway. The best time to check for a traffic jam is during rush hour. The corresponding clinical scenario is stress testing. There are three major roadways in the heart: left anterior, left circumflex, and right, each with branches (forks). The two left major vessels stem from a short but treacherous left main (“widow maker”). A temporary traffic jam results in symptoms of impaired delivery (angina, from hunger due to late delivery of food). Alternatively, a prolonged traffic disruption can result in suicidal tissue destruction (starvation). A fixed obstruction consists of potholes and landslides resulting in a persisting shutdown of half or more of the lanes in the highway. An unstable plaque consists of a less severe abnormality that can cause accidents (plaque rupture, local hemorrhage, sudden occlusion). A road may shutdown not only from progressive road damage, but also a truck can flip over and shutdown a relatively clean roadway.

Among patients who had recent coronary imaging prior to the onset of a heart attack, half do not have occlusive lesions. Instead of slow progressive reduction in vessel diameter leading to a critically severe flow reduction, the mechanism in the cases of no severe narrowing is attributed to unstable plaque, meaning plaque with thin fibrous caps that rupture, causing sudden thrombosis. Stress tests focus on detection of fixed obstructions and do not warn who has unstable plaque. Thus the next great frontier for coronary imaging is not just to identify flow reducing lesions, but also to identify unstable plaque even if it is not currently flow limiting. This article presents candidate imaging methods and their current capabilities.

Coronary imaging methods include:

intra-coronary ultrasound (IVUS)

optical coherence imaging (fiberoptic)

computed tomographic xray angiography (CTA)

magnetic resonance angiography (MRA)

near infra-red spectroscopic imaging (NIRS)

NIRS-IVUS Imaging To Characterize the Composition and Structure of Coronary Plaques

authored by highly experienced interventional cardiologists expert in the field of coronary plaque characterization, contains a detailed description of the new NIRS-IVUS combination catheter, and the clinical information obtained during its use in over 90 hospitals in over 10 countries. Case vignettes, cohort outcomes, reviews, and plans for future studies are also presented. It is our hope that this information will be useful in the near term to those seeking to improve PCI. For the longer term, we believe that the NIRS-IVUS system is an excellent candidate for evaluation as a detector of vulnerable plaque. Success in the prospective studies that are planned will make it possible to detect vulnerable plaques and thereby enhance efforts to prevent coronary events.

VH-IVUS, OCT, and NIRS can assist in the detection and evaluation of lipid core plaque. Comparative studies have shown important differences between modalities, but are all limited from lack of comparison with the gold standard of histology. Given the different strengths and weaknesses of each modality, combination imaging will likely provide the best results.41 Further refinement of the clinical implications of LCP detection and its impact on optimizing treatment strategy selection will stimulate advances in LCP detection imaging.

OCT and NIRS can image through calcified lesions, whereas IVUS cannot. LCPs are often accompanied by neovascularization, which can only be visualized by OCT. VH-IVUS may classify stents, which usually appear white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”), although this does not appear to be a limitation for NIRS and OCT.54

The miniaturization of medical devices and the progress in image processing have allowed the development of a multitude of intravascular imaging modalities that permit more meticulous examination of coronary pathology. However, these techniques have significant inherent limitations that do not allow a complete and thorough assessment of coronary anatomy. To overcome these drawbacks, fusion of different invasive and noninvasive imaging modalities has been proposed. This integration has provided models that give a more detailed understanding of coronary artery pathology and have proved useful in the study of the atherosclerotic process. In this review, the authors describe the currently available hybrid imaging approaches, discuss the technological innovations and efficient algorithms that have been developed to integrate information provided by different invasive techniques, and stress the advantages of the obtained models and their potential in the study of coronary atherosclerosis.

Intravascular ultrasound (IVUS) is used before and after intervention and at follow-up to assess the quality of the acute result as well as the long-term effects of stent implantation. Virtual histology (VH) IVUS classifies tissue into fibrous and fibrofatty plaque, dense calcium, and necrotic core. Although most interventional procedures include stent implantation, VH IVUS classification of stent metal has not been validated. In this study, the VH IVUS appearance of acutely implanted stents was assessed in 27 patients (30 lesions). Most stent struts (80%) appeared white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”); 2% appeared just white, and 17% were not detectable (compared with grayscale IVUS because of the software-imposed gray medial stripe). The rate of “white surrounded by red” was similar over the lengths of the stents; however, undetectable struts were mostly at the distal edges (31%). Quantitatively, including the struts within the regions of interest increased the amount of “calcium” from 0.23 ± 0.35 to 1.07 ± 0.66 mm2 (p <0.0001) and the amount of “necrotic core” from 0.59 ± 0.65 to 1.31 ± 0.87 mm2 (p <0.0001). Most important, because this appearance occurs acutely, it is an artifact, and the red appearance should not be interpreted as peristrut inflammation or necrotic core when it is seen at follow-up. In conclusion, acutely implanted stents have an appearance that can be misclassified by VH IVUS as “calcium with or without necrotic core.” It is important not to overinterpret VH IVUS studies of chronically implanted stents when this appearance is observed at follow-up. A separate classification for stent struts is necessary to avoid these misconceptions and misclassifications.

Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular.

Dr. Muller is a full-time employee of Infraredx, Inc from which he receives salary and equity.

Address for Correspondence: Email: ryan.madder@spectrumhealth.org

The search for the vulnerable plaque has been a lengthy endeavor requiring the work of multiple individuals and institutions over many years. It is disappointing that in more than 2 decades since the “vulnerable plaque” concept was formulated, over 40 million coronary events have occurred. However, it is encouraging that positive answers are now available for most of the questions related to a vulnerable plaque detection and treatment strategy. As shown in Table 1, most of the essential preconditions of a successful vulnerable plaque strategy are present. This positive information has accelerated the pace of work in this area. The pathophysiology of coronary events is well-understood; powerful imaging methods are available; and therapies, both existing and novel, may well be effective (although appropriately powered randomized trials are required to demonstrate their safety and effectiveness). The time is approaching for the conduct of prospective outcome trials to determine the value of a vulnerable plaque strategy for more effective prevention of coronary events.

Table 1. Essential Components of a Strategy to Prevent Coronary Events by the Detection and Treatment of Vulnerable Plaques

Essential Components

Evidencefrom Published Research

Pathophysiology of Coronary Events

• Are the causes of coronary events known?

Yes

Constantinides and others have shown that most coronary events are caused by rupture of a thin-capped LRP with subsequent formation of an occlusive thrombus.1-5

• Are LRPs focal?

Yes

Cheruvu et al demonstrated that ruptures and TCFA occupy less than 4% of the length of arteries studied at autopsy.8

• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for secondary prevention?

Probably

Bosch et al demonstrated that for patients already undergoing invasive imaging, the added costs of detection and treatment of VP are likely to be less than the cost of second events, leading to a cost-saving approach that also improves health.38

• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for primary prevention?

?

Bosch et al: For primary prevention the cost of screening would be greater than for secondary prevention. Cost-effectiveness would depend upon cost, the accuracy of detection, and effectiveness of therapy.38

Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.

Address for correspondence: Email: p.w.j.c.serruys@erasmusmc.nl

The advent of intravascular imaging in the 1980s allowed us to studyin vivo plaque morphology and its prognostic implications.

Angioscopy and intravascular ultrasound (IVUS) were the first imaging techniques that provided information about the composition of plaque and allowed detection of its lipid component.7,8

However, the first applications of these modalities in the clinical setting not only underscored their potential value in the study of atherosclerosis but also highlighted their limitations in characterizing atheroma.9-11 Therefore an effort was made over the last few years to develop advanced techniques that would allow more reliable assessment of a plaque’s composition. Today several modalities are available for this purpose including:

the radiofrequency analysis of the IVUS backscatter signal (RF-IVUS),

near-infrared spectroscopy (NIRS),

optical coherence tomography (OCT),

magnetic resonance spectroscopy,

intravascular magnetic resonance imaging,

Raman spectroscopy,

photoacoustic imaging, and

time resolved spectroscopic imaging (Figure 1).

Some of these modalities are still in their infancy, while others have already been used in the clinical setting providing robust evidence about the prognostic implications of the differing compositions of the plaque. The aim of this review article is to present the most recent evidence about the long-term consequences of the atheroma’s phenotype.

Current Evidence from NIRS-based Clinical Studies

NIRS relies on the principle that different organic molecules absorb and scatter NIRS light to different degrees and wavelengths. Recent advances in device technology enabled the development of a catheter suitable for assessing the plaque in human coronaries that is able to emit NIR light and acquire the scattered signal. Spectral analysis of the obtained signal provides a color-coded display, called a chemogram (Figure 1C), which provides the probability that lipid core is present in the superficial plaque (studied depth approximately: 1 mm). Several studies have examined the reliability of this technique using histology as the gold standard and demonstrated a high overall accuracy in detecting lipid-rich plaques while others demonstrated its feasibility in the clinical setting.19-20

The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis (NCT01789411) – NIRS sub-study was the first prospective trial designed to evaluate the prognostic implications of an increased lipid component, as detected by NIRS, in coronary plaques. Two hundred three patients that underwent X-ray angiography, and PCI if it was indicated, had NIRS in a non-culprit coronary segment and were followed-up for 1 year. Twenty-eight patients sustained a MACE during the follow-up period; 21 of these events were non-culprit lesion related. Lipid plaque burden index appeared to be an independent predictor of MACE (hazard ratio: 4.04, 95% confidence interval: 1.33-12.29; P=0.01).

Currently, the Chemometric Observation of Lipid Rich Plaque of Interest in Native Coronary Arteries (COLOR, NCT00831116) registry is recruiting patients. This study is planning to recruit 2000 patients that will be investigated with NIRS imaging, and aims to examine the association between the presence of a necrotic core in the atheroma and subsequent coronary events. Preliminary results indicate that the absence of lipid-rich plaques is related with better outcomes (www.infraredx.com/the-color-registry).

Current Evidence From OCT-based Clinical Studies

OCT imaging with its high resolution appears able to provide detailed assessment of the superficial plaque and visualize structures that are unseen by other techniques such as the presence of micro calculations of thin-capped fibroatheroma (TCFA). However, a significant limitation of this technique is its poor penetration (1-2 mm), which does not permit through visualization of plaque burden, as well as its low capacity in differentiating lipid from calcific tissue when these are deeply embedded in the vessel wall.21

In this analysis, 53 patients who underwent PCI had OCT imaging in non-obstructive lesion sat baseline and repeat angiography at 7 months follow-up. They found that plaques with a TCFA phenotype, exhibiting vessel walldiscontinuities, macrophages, neo-vessels, and thrombi were morelikely to progress and cause significant angiographic obstructions.22

Future Perspective in Plaque Imaging – Conclusions

Cumulative data derived from intravascular imaging studies have provided robust evidence about the prognostic implications of plaque’s composition and burden, and demonstrated a strong association between the presence of lipid-rich plaques and future cardiovascular events. Plaque pathology and quantification of lipid components is done by hybrid catheters able to acquire different intravascular imaging data.23

5.Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediatelesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council onArteriosclerosis, American Heart Association. Circulation. 1994;89:2462-2478.

6.ﾭrotic lesions and a histological classification of atherosclerosis. A report from the Committee onVascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation.1995;92:1355-1374.

Disclosures: Dr. Goldstein is a consultant for and owns equity in Infraredx, Inc. Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular. Dr. Dixon reports no financial relationships or conflicts

Abstract:

Percutaneous coronary intervention (PCI) is associated with distal embolization complications, including peri-procedural myocardial infarction (PPMI), including no-reflow, in 3%-15% of cases. These complications are predominantly related to distal embolization of lipid core plaque (LCP) components. Catheter-based near-infrared spectroscopy (NIRS) provides rapid, automated detection of LCPs, the magnitude of which appears associated with a high-risk of PPMI. Employing this technique may facilitate development of preventive measures such as embolic protection devices (EPDs).

Disclosures: Dr. Kovacic is supported by National Institutes of Health Grant K08HL111330 and has received research support from AstraZeneca. Dr. Kini acknowledges honoraria from Medscape and has received research grant support from InfraReDx.

A new group of terms is slowly creeping in to the atherosclerotic disease lexicon: “Lipid Arc,” “Lipid Core Plaque,” “Lipid-Rich Plaque,” “Lipid Core Burden Index” and other similar phrases. While clinicians and researchers have long been aware of the central importance of lipid in the biology of atherosclerosis, the growing use of these terms is driven by the recent widespread use of novel imaging modalities that provide accurate detection, and even quantification, of the extent of lipid that is contained within the core of an atherosclerotic plaque. Our ability to detect and quantify lipid in plaques is opening up new therapeutic opportunities for modifying the atherosclerotic disease process, which may ultimately be of benefit to patients.

At the present time there are 3 methods that are commonly used to measure the extent of lipid in atherosclerotic plaques. Perhaps most familiar of these is coronary computer tomographic (CT) scanning. While more commonly used to quantitate calcification or luminal stenosis, CT scanning is readily able to quantitate the extent of lipid associated with an atherosclerotic lesion. However, while several studies have reported various Hounsfield Unit (HU)-based criteria to distinguish lipid-rich from fibrous plaques, the HU cut-off points have so far been inconsistent. The use of CT for detecting lipid-rich plaque is further limited by its relatively low spatial resolution and the fact that the HU values for distinguishing between fibrous and lipid-rich plaques are overlapping.1 In contrast, optical coherence tomography (OCT) offers perhaps the greatest spatial resolution of all clinically available coronary imaging devices. OCT can offer exquisite detail of abluminal coronary artery anatomy, including detection of lipid core plaque. However, while automated systems are being developed, at the present time the quantitation of lipid by OCT is a somewhat specialized process that typically involves detailed off-line analysis.

A specific intra-coronary imaging catheter for the quantitation of coronary artery lipid content is now available and FDA approved: diffuse reflectance near-infrared spectroscopy (NIRS). The application of NIRS to identify lipid deposition within coronary arteries has been validated ex vivo2-5 and in vivo.6,7 Although NIRS itself is essentially only able to detect and quantitate lipid, design changes and technological advances to this catheter have now made it possible to combine intravascular ultrasound (IVUS) and NIRS technology on a single instrument. In one of the few clinical studies published to date using this device, NIRS has already shown that a high lipid burden in a target lesion undergoing percutaneous coronary intervention (PCI) is associated with an increased likelihood of peri-procedural myocardial infarction.7

It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. REVERSAL,8 ASTEROID,9 and more recently the SATURN II10 trial showed that in patients with coronary artery disease (CAD), lipid lowering with high-dose statin therapy reduced progression of plaque atheroma burden, even causing plaque regression of some lesions. However, while reduction in atheroma burden and plaque size are important anatomical endpoints, a major unresolved question had been the mechanism of action of statins and the unanswered question of whether they reduce plaque lipid content. Indeed, a high burden of plaque lipid is one of the cardinal features of a rupture-prone vulnerable lesion.11 Therefore, the ability to reduce plaque lipid content may have important effects on lesion stability and therefore, might impact clinical endpoints.

The advent of sensitive imaging tools for the evaluation of plaque lipid content has paved the way for the investigation of potential pharmacological therapies for lipid core plaque. In particular, the ability of NIRS to provide an automated quantitation of plaque lipid provides a ready-made platform for this task. We recently completed the YELLOW study of high-dose statin therapy for the potential reduction of coronary artery lipid content as assessed by NIRS. We randomized 87 patients with multivessel CAD undergoing elective PCI to rosuvastatin 40 mg daily vs conventional statin therapy. Following PCI of the culprit lesion, non-culprit lesions with a fractional flow reserve (FFR) <0.8 were interrogated using IVUS and NIRS. Changes in plaque composition were assessed after 6-12 weeks during follow-up angiography. The core finding of this study was that high-dose statin therapy was associated with significant reductions in the lipid content of coronary atherosclerotic plaques. Interestingly, despite reduced plaque lipid content, in this relatively short time period concordant changes in gross lesion characteristics such as total atheroma volume or % plaque burden were not observed.12 In short, the YELLOW study identified that even before gross atheroma regression occurs, lipid removal from plaques is an early event upon initiation of high-dose statin therapy. Furthermore, the results of the YELLOW study are concordant with the known acute benefits of statin therapy in patients presenting with acute coronary syndromes, where the early introduction of these agents is known to be of clinical benefit.13 While the YELLOW study was the first of this nature and the results remain to be replicated in a larger trial, these findings have revived interest in the concept of the “vulnerable plaque” because it appears possible that by causing lipid core reduction over a just few weeks, high-dose statin therapy may have rapid plaque stabilizing effects. We are now embarking on the YELLOW II study, where we will further explore the utility of high-dose rosuvastatin for the early reduction of plaque lipid content and potential mechanistic pathways.

What other agents might have therapeutic efficacy for lipid core reduction? This question is perhaps more complex than it might first appear, because at the present time we do not know the specific mechanism whereby high-dose rosuvastatin causes lipid reduction in plaques. Theoretically it may be due to reduced LDL, increased HDL, other mechanisms or a combination of these effects. Potentially, other agents that are already available such as bile acid sequestrants, ezetimibe, and fibrates may have a weak lipid core reducing effect. However, we would underscore the fact that at the present time the utility of these agents is speculative, and no other agent (apart from high-dose rosuvastatin in the YELLOW study) has been shown to reduce lipid content in vivo in human plaques. Furthermore, given the fact that these other agents are far less potent in their overall effect than rosuvastatin 40 mg/day, it may be clinically challenging to determine if they have efficacy for lipid core reduction beyond that of statins.

In addition to pharmacotherapy, it must be remembered that we have several non-pharmacological treatments in our armamentarium that may impact lipid core reduction. For example, exercise is known to be associated with reduced plaque lipid content,14 and proper adherence to current guidelines with respect to lifestyle and diet are of paramount importance in any patient in whom it is considered desirable to reduce plaque lipid content.

Looking ahead, there are several emerging and investigational agents that may hold promise for lipid core reduction. Microsomal triglyceride transfer protein (MTP) is expressed in the liver, intestine, and the heart and is required for the proper assembly of VLDL and chylomicrons. In animals, treatment with an MTP inhibitor leads to a rapid reduction in plasma lipid levels, with a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques.15 On December 21, 2012, the first of the MTP inhibitors was approved for clinical use. Lomitapide (marketed as Juxtapid) was approved by the FDA as an adjunct to a low fat diet and other lipid-lowering treatments for patients with homozygous familial hypercholesterolemia. However, concerns have been raised due to hepatic side effects and liver toxicity. As a result, lomitapide will carry a boxed warning and will only be available through a restricted program.16 Another new drug that was recently given restricted approval in the US for homozygous familial hypercholesterolemia is mipomersen. This agent is an antisense therapeutic that targets messenger RNA for apolipoprotein B, leading to reduced apoB protein and LDL levels. While showing efficacy for lowering LDL,17 safety concerns have thus far prohibited this agent from gaining approval for use in Europe. PCSK9 inhibitors are yet another novel class of agents that may hold promise for reducing lipid core plaque. PCSK9 is involved in the degradation of the LDL receptor (LDLR), and by inhibiting PCSK9 it is believed that this permits more LDL receptors to remain active and participate in LDL removal from the blood, thereby reducing plasma LDL and cholesterol levels. Denis et al18 recently demonstrated that gene inactivation of PCSK9 in mice reduced aortic cholesterol accumulation and atherosclerotic lesion development in atherosclerosis-prone mice. Based on their powerful LDL lowering effect, intense efforts are currently underway to develop clinically efficacious PCSK9 inhibitors with several agents already moving to phase II/III human studies.19 While all of these new and emerging therapies are cause for optimism, the recent experience with CETP-inhibitors and the overall failure of this class so far to stand up to rigorous testing as HDL raising agents in phase III studies20,21 serves to remind us that not all “promising future therapies” survive through the arduous clinical testing pipeline.

In conclusion, there is renewed interest in the concept of “plaque regression” and pharmacological therapy for “lipid core reduction.” This has been driven by our increasing ability to image and quantify these phenomena, and more recently by the provocative findings that high-dose statin therapy may achieve both of these clinical endpoints. Further studies are now required to evaluate novel agents, define mechanisms of action and, most importantly, to confirm that atherosclerotic lipid core reduction is associated with plaque stabilization and fewer clinical endpoints.

Conclusions:

The authors concluded that proximal LAD location was associated with higher rates of MI during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE.

Perspective:

This post hoc analysis of a prospective, multicenter study reports no difference in the rates of death, MACE, or TVF at 4 years according to intervention at a proximal LAD or nonproximal LAD lesion. The occurrence of the predefined primary endpoint of stent thrombosis was also not dependent on whether a proximal LAD or nonproximal LAD site was treated. However, of note, stenting of proximal LAD lesions was associated with significantly higher rates of MI compared with stenting of nonproximal LAD lesions. Overall, these findings appear to suggest that proximal LAD lesions may not have additional risk in the contemporary DES era, but the higher risk of MI needs to be studied further. Future studies should compare longer-term clinical outcomes between proximal LAD PCI with DES and minimally invasive left internal mammary artery to LAD.

Stenting for Proximal LAD Lesions

Curator: Aviva Lev-Ari, PhD, RN

Michael Reinhardt • First, the media really should not be calling this “stent surgery” its a stent procedure just ask any post-CABG patient… Anyway it really is not possible to determine whether or not is was “unnecessary” without all the relevant patient data; which coronary vessel(s) involved, percent stenosis, etc. Actually I find it interesting that they apparently decided to stent the former president on the basis of a CT Angiogram which is not the standard of care for coronary imaging. I have to assume they performed an additional testing like a CT perfusion analysis and saw a clinically relevant defect and this support the decision to stent. Regarding the post-stent drugs cloplidigrel is not a benign drug but benefits far outweigh the downside of a sub-acute thrombosis which might result in a more serious future event = acute MI.

Rafael Beyar • This was absolutely an indicated procedure and almost all rational physician will treat a young patient with proximal LAD lesions with either a stent or bypass surgery

Dov V Shimon MD • No doubt! Proximal (‘close to origin’) LAD lesions are the leading “Widow makers”. Reestablishing of flow in the artery is saving from cardiac damage and death. Drug eluting stent have 2nd and 3rd generations with very low and acceptable reclosure rates and almost no abrupt closure (thrombosis). True, CTA is a screening test, but it astablishes the need for diagnostic and therapeutic angiogram. We, heart surgeons can provide long-term patency to the LAD using LIMA arterial bypass. The current advantage of stent is the incovenience and pain of surgery. Any responsible physician would opt the procedure even for himself, his relatives , his patients and for definitely for GW Bush.

Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?

Source

Abstract

OBJECTIVES:

The objective of this study was to compare the long-term outcome of patients with an isolated high-grade stenosis of the left anterior descending (LAD) coronary artery randomized to percutaneous transluminal coronary angioplasty with stenting (PCI, stenting) or to off-pump coronary artery bypass grafting (surgery).

METHODS:

Patients with an isolated high-grade stenosis (American College of Cardiology/American Heart Association classification type B2/C) of the proximal LAD were randomly assigned to stenting (n=51) or to surgery (n=51) and were followed for 3-5 years (mean 4 years). Primary composite endpoint was freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiac death, myocardial infarction, stroke and repeat target vessel revascularization. Secondary endpoints were angina pectoris status and need for anti-anginal medication at follow-up. Analysis was by intention to treat.

RESULTS:

MACCEs occurred in 27.5% after stenting and 9.8% after surgery (P=0.02; absolute risk reduction 17.7%). Freedom from angina pectoris was 67% after stenting and 85% after surgery (P=0.036). Need for anti-anginal medication was significantly lower after surgery compared to stenting (P=0.002).

CONCLUSION:

Patients with an isolated high-grade lesion of the proximal LAD have a significantly better 4-year clinical outcome after off-pump coronary bypass grafting than after PCI.

Was George Bush’s stent surgery really unnecessary?

Ever since President George W. Bush had stent surgery last Tuesday to open a blocked artery, leading physicians who weren’t involved in his care have wondered publically why he had this “unnecessary” procedure. Large clinical trials have demonstrated that stent placement doesn’t extend lives or prevent a future heart attack or stroke in those with stable heart disease.

What’s more, Bush could wind up with complications like a reblockage where the stent was placed or excessive bruising or internal bleeding from the blood thinners that he must take likely for the next year.

“In people who are not having symptoms, the American Heart Association says you should not do a stress test,” Besser said, “since the value of opening that artery is to relieve the symptoms.”

Cleveland Clinic cardiologist Dr. Steve Nissen agreed in his interview with USA Today. Bush, he said, likely “got the classical thing that happens to VIP patients, when they get so-called executive physicals and they get a lot of tests that aren’t indicated. This is American medicine at its worst.”

But none of these doctors actually treated Bush or examined his medical records, so I’m a little surprised they’re making such firm calls.

Bush, an avid biker who recently completed a 100-kilometer ride, probably shouldn’t have had the exercise stress test if he wasn’t having any heart symptoms. “Routine stress testing used to be done 20 years ago, but isn’t recommended any longer since it doesn’t have any benefit,” said Brigham and Women’s cardiologist Dr. Christopher Cannon.

But Bush’s spokesman insisted the stent was necessary after followup heart imaging via a CT angiogram “confirmed a blockage that required opening.”

Cannon said Bush’s doctors may have seen signs that blood flow wasn’t getting to a significant part of the heart muscle, a condition known as ischemia. Researchers have found that those with moderate to severe ischemia appear to experience a reduction in fatal heart attacks when they have a stent placement along with medical therapy, rather than just taking medications alone. (Larger studies, though, are needed to confirm this finding.)

“If a blockage occurs at the very start of the artery and it’s extensive—95 percent blocked—then chances are it will cause significant ischemia,” Cannon said. While severe ischemia usually causes light-headedness or dizziness during exercise, Bush may have had more moderate ischemia that didn’t cause such symptoms.

It’s impossible to know for certain, he added, without seeing his medical records firsthand.

President Bush’s unnecessary heart surgery

Vinay Prasad is chief fellow of medical oncology at the National Cancer Institute and the National Institutes of Health. Adam Cifu is a professor of medicine at the University of Chicago.

Former president George W. Bush, widely regarded as a model of physical fitness, received a coronary artery stent on Tuesday. Few facts are known about the case, but what is known suggests the procedure was unnecessary.

If Mr. Bush had visited a general internist practicing sound, evidence-based care, he would not have had cardiac testing. Instead, the doctor would have had conducted age-appropriate cancer screening. For the former president, this would include only colon cancer screening. It no longer would include even prostate-specific antigen testing for cancer. The doctor would have screened for cholesterol, checked for hypertension and made sure the patient was up to date on age-appropriate vaccinations, including those for pneumococcal pneumonia and shingles. Presumably Mr. Bush got these things, and he got the cardiac test as well.What value does a stress test add for an otherwise healthy 67-year-old?No study has shown that this examination improves outcomes. The trials that have been done for so-called routine stress testing examined higher-risk patients. They found that performing stress tests on people at high risk of cardiovascular disease may detect blockages but does not improve symptoms or survival. Routine stress testing does, however, increase the use of procedures such as coronary stenting.Unfortunately, Mr. Bush, like many VIPs, may be paying the price of these in-depth investigations. His stress test revealed an abnormality, prompting another test: a CT angiogram. This study showed a blockage, which was stented open during an invasive procedure. It is worth noting that at least two large randomized trials show that stenting these sorts of lesions does not improve survival. Because Mr. Bush had no symptoms, it is impossible that he felt better after these procedures.

Instead, George W. Bush will have to take two blood thinners, aspirin and Plavix, for at least a month and probably a year. (The amount of time a blood thinner is needed depends on the type of stent placed). While he takes these medications, he will have a higher risk of bleeding complications with no real benefit.

Although this may seem like an issue important only to the former president, consider the following: Although the price of excessive screening of so-called VIPs is usually paid for privately, follow-up tests, only “necessary” because of the initial unnecessary screening test, are usually paid for by Medicare, further stressing our health-care system. The media coverage of interventions like Mr. Bush’s also leads patients to pressure their own doctors for unwarranted and excessive care.

“Coronary” describes the crown-like position of arteries on the heart that provide its nutrient blood supply. The heart does not live off of the blood in its chambers, but rather receives its nutrient perfusion from branches of the aorta, like all other organs. The most relied on method to exam coronary artery anatomy is angiography – xray image movies obtained while the blood is opacified by injection of iodine (high atomic number to block xrays) to provide a contrast between arterial flow channel (the lumen) and the surrounding tissues. Computed tomography is providing a second-best alternative with 3D reconstructions that can be obtained less invasively (no catheters), but it often fails to see the posterior descending artery (PDA) well, and is lower in resolution (point-discrimination detail) than xray angiography (XRA). Magnetic resonance angiography (MRA) comes in as a distant third place method for examining coronary anatomy (lower quality, lower reliability), but non-invasive with no ionizing radiation. A major goal of defining coronary anatomy in individual patients is to identify coronary artery disease (CAD) and to clarify best options for management – to relieve angina and to avoid adverse consequences, e.g., heart attacks (myocardial infarction), heart failure (CHF) and death. The COURAGE trial showed that for many, aggressive medical management with statins and blood pressure control may obviate need for percutaneous or surgical interventions to control angina and minimize the risk of adverse outcomes. Patients with blockage of the left main coronary artery, or two vessel blockage including proximal left anterior descending (LAD) especially with below normal ejection fraction may be better off in the long run with bypass surgery. Therefore less invasive imaging sufficient to rule out left main disease and proximal LAD disease may suffice for decision making (except that the BARI trial results have not been overturned in favoring bypass surgery for diabetics).

On the left an overview of the coronary arteries in the anterior projection.

Coronary anatomy and anomalies

Left Main or left coronary artery (LCA)

Left anterior descending (LAD)

diagonal branches (D1, D2)

septal branches

Circumflex (Cx)

Marginal branches (M1,M2)

Right coronary artery

Acute marginal branch (AM)

AV node branch

Posterior descending artery (PDA)

RCA, LAD and Cx in the anterior projection

On the left an overview of the coronary arteries in the lateral projection.

Left Main or left coronary artery (LCA)

Left anterior descending (LAD)

diagonal branches (D1, D2)

septal branches

Circumflex (Cx)

Marginal branches (M1,M2)

Right coronary artery

Acute marginal branch (AM)

AV node branch

Posterior descending artery (PDA)

RCA, LAD and Cx in the right anterior oblique projection
On the left an overview of the coronary arteries in the lateral projection.

Left Main or left coronary artery (LCA)

Left anterior descending (LAD)

diagonal branches (D1, D2)

septal branches

Circumflex (Cx)

Marginal branches (M1,M2)

Right coronary artery

Acute marginal branch (AM)

AV node branch

Posterior descending artery (PDA)

RCA, LAD and Cx in the lateral projection

Left Coronary Artery (LCA)

The left coronary artery (LCA) is also known as the left main.
The LCA arises from the left coronary cusp.

The aortic valve has three leaflets, each having a cusp or cup-like configuration.
These are known as the left coronary cusp (L), the right coronary cusp (R) and the posterior non-coronary cusp (N).
Just above the aortic valves there are anatomic dilations of the ascending aorta, also known as the sinus of Valsalva. The left aortic sinus gives rise to the left coronary artery.
The right aortic sinus which lies anteriorly, gives rise to the right coronary artery.
The non-coronary sinus is postioned on the right side.

The LCA divides almost immediately into the circumflex artery (Cx) and left anterior descending artery (LAD).
On the left an axial CT-image.
The LCA travels between the right ventricle outflow tract anteriorly and the left atrium posteriorly and divides into LAD and Cx.

On the image on the left we see the left main artery dividing into

Cx with obtuse marginal branch (OM)

LAD with diagonal branches (DB)

On volume rendered images the left atrial appendage needs to be removed to get a good look on the LCA.

In 15% of cases a third branch arises in between the LAD and the Cx, known as the ramus intermedius or intermediate branch.
This intermediate branche behaves as a diagonal branch of the Cx.

Left Anterior Descending (LAD)

The LAD travels in the anterior interventricular groove and continues up to the apex of the heart.
The LAD supplies the anterior part of the septum with septal branches and the anterior wall of the left ventricle with diagonal branches.
The LAD supplies most of the left ventricle and also the AV-bundle.Mnemonic: Diagonal branches arise from the LAD.

CT image of the LAD in RAO projection

The diagonal branches come off the LAD and run laterally to supply the antero-lateral wall of the left ventricle.
The first diagonal branch serves as the boundary between the proximal and mid portion of the LAD (2).
There can be one or more diagonal branches: D1, D2 , etc.

Circumflex (Cx)

The Cx lies in the left AV groove between the left atrium and left ventricle and supplies the vessels of the lateral wall of the left ventricle.
These vessels are known as obtuse marginals (M1, M2…), because they supply the lateral margin of the left ventricle and branch off with an obtuse angle.
In most cases the Cx ends as an obtuse marginal branch, but 10% of patients have a left dominant circulation in which the Cx also supplies the posterior descending artery (PDA).Mnemonic: Marginal branches arise from the Cx and supply the lateral Margin of the left ventricle.

Circumflex and LAD seen in Lateral projection

Right Coronary Artery (RCA)

The right coronary artery arises from the anterior sinus of Valsalva and courses through the right atrioventricular (AV) groove between the right artium and right ventricle to the inferior part of the septum.
In 50-60% the first branch of the RCA is the small conus branch, that supplies the right ventricle outflow tract.
In 20-30% the conus branch arises directly from the aorta.
In 60% a sinus node artery arises as second branch of the RCA, that runs posteriorly to the SA-node (in 40% it originates from the Cx).
The next branches are some diagonals that run anteriorly to supply the anterior wall of the right ventricle.
The large acute marginal branch (AM) comes off with anacute angle and runs along the margin of the right ventricle above the diaphragm.
The RCA continues in the AV groove posteriorly and gives off a branch to the AV node.
In 65% of cases the posterior descending artery (PDA) is a branch of the RCA (right dominant circulation).
The PDA supplies the inferior wall of the left ventricle and inferior part of the septum.

RCA, LAD and LCx in Anterior projection

On the image on the far left we see the most common situation, in which the RCA comes off the right cusp and will provide the conus branch at a lower level (not shown).
On the image next to it, we see a conus branch, that comes off directly from the aorta.

LEFT: RCA comes off the right sinus of Valsalva
RIGHT: Conus artery comes off directly from the aorta

The large acute marginal branch (AM) supplies the lateral wall of the right ventricle.
In this case there is a right dominant circulation, because the posterior descending artery (PDA) comes off the RCA.

Coronary Anomalies

Coronary anomalies are uncommon with a prevalence of 1%.
Early detection and evaluation of coronary artery anomalies is essential because of their potential association with myocardial ischemia and sudden death (3).
With the increased use of cardiac-CT, we will see these anomalies more frequently.

Coronary anomalies can be differentiated into anomalies of the origin, the course and termination (Table).

The illustration in the left upper corner is the most common and clinically significant anomaly.
There is an anomalous origin of the LCA from the right sinus of Valsalva and the LCA courses between the aorta and pulmonary artery.
This interarterial course can lead to compression of the LCA (yellow arrows) resulting in myocardial ischemia.

The other anomalies in the figure on the left are not hemodynamically significant.

Interarterial LCA

On the left images of a patient with an anomalous origin of the LCA from the right sinus of Valsalva and coursing between the aorta and pulmonary artery.
Sudden death is frequently observed in these patients.

ALCAPA

On the left images of a patient with an anomalous origin of the LCA from the pulmonary artery, also known as ALCAPA.
ALCAPA results in the left ventricular myocardium being perfused by relatively desaturated blood under low pressure, leading to myocardial ischemia.
ALCAPA is a rare, congenital cardiac anomaly accounting for approximately 0.25-0.5% of all congenital heart diseases.
Approximately 85% of patients present with clinical symptoms of CHF within the first 1-2 months of life.

Myocardial bridging

Myocardial bridging is most commonly observed of the LAD (figure).
The depth of the vessel under the myocardium is more important that the lenght of the myocardial bridging.
There is debate, whether some of these myocardial bridges are hemodynamically significant.

Fistula

On the image on the left we see a large LAD giving rise to a large septal branch that terminates in the right ventricle (blue arrow).

Left to right shunt: septal branch of LAD teminates in right ventricle

*Meta-analysis of results of 3 trials at 1 year. Patients with single-vessel disease were studied.[22] †Meta-analysis of results of 3 trials at 1 year. Patients with multivessel disease were studied.[22]

‡Reported results are for 5-year follow-up. Patients with multivessel disease were studied.[21]

According to a pooled analysis of 3 CHAMPION trials—CHAMPION-PCI , CHAMPION-PLATFORM , and CHAMPION-PHOENIX—cangrelor can reduce the risk of periprocedural thrombotic complications of PCI.[1, 2, 3] The 3 trials included patients with ST-elevation MI (STEMI), non-STEMI, and stable CAD who were randomly assigned to receive either cangrelor or control therapy consisting of either clopidogrel or placebo.

The primary outcome in this analysis was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours.[2] The frequency of this outcome was significantly lower in cangrelor-treated patients than in control subjects (absolute difference, 1.9%; relative risk reduction [RRR], 19%). Stent thrombosis was also reduced in the cangrelor-treated group (absolute difference, 0.3%; RRR, 41%). Primary safety outcomes were comparable in the 2 groups, but cangrelor-treated patients had a higher rate of mild bleeding.

Indications and contraindications

In an asymptomatic or mildly symptomatic patient, objective evidence of a moderate-sized to large area of viable myocardium or moderate to severe ischemia on noninvasive testing is an indication for PCI. Angiographic indications include hemodynamically significant lesions in vessels serving viable myocardium (vessel diameter >1.5 mm).

Clinical contraindications for PCI include the presence of any significant comorbid conditions (this is a relative contraindication). Angiographic contraindications include the following:

Left main stenosis in a patient who is a surgical candidate (except in carefully selected patients[4] )

In patients with stable angina, medical therapy is recommended as first-line therapy unless one or more of the following indications for cardiac catheterization and PCI or CABG are present:

A change in symptom severity

Failed medical therapy

High-risk coronary anatomy

Worsening left ventricular (LV) dysfunction

American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines on the management of unstable angina/non-STEMI recommend that an early invasive approach (angiography and revascularization within 24 hours) should be used to treat patients presenting with the following high-risk features[5] :

Recurrent angina at rest or low level of activity

Elevated cardiac biomarkers

PCI in the past 6 months or prior CABG

New ST-segment depression

Elevated cardiac biomarkers

High-risk findings on noninvasive testing

Signs or symptoms of heart failure or new or worsening mitral regurgitation

Now we are reporting an Original Contribution on this subject which includes also Prior History of PCI, a factor NOT included in the other studies. The major conclusions are the following three:

In a contemporary cohort of STEMI patients undergoing primary PCI, a history of prior CABG was found to be an independent predictor of in-hospital mortality.

In contrast, despite more comorbidities at the time of STEMI, patients with prior PCI had no significant difference in the rates of death, stroke, or periprocedural MI when compared to a STEMI population without prior coronary revascularization.

Thus, only prior surgical — and not percutaneous — revascularization should be considered a significant risk factor in the setting of primary PCI.

Number 1, above is related to patient medical history of cardiovascular disease SEVERITY prior to CABG

Number 2, above indicates that patients can tolerate and benefit several cycles of PCI and stent implantation rather than PCI being a determinant predictor of future prognosis

Number 3, above is as well related to patient medical history of cardiovascular disease SEVERITY prior to CABG

Abstract : While the impact of prior coronary artery bypass graft surgery (CABG) on in-hospital outcomes in patients with STelevation myocardial infarction (STEMI) has been described, data are limited on patients with prior percutaneous coronary intervention (PCI) undergoing primary PCI in the setting of an STEMI. The aim of the present study was to assess the effect of previous revascularization on in-hospital outcomes in STEMI patients undergoing primary PCI. Between January 2004 and December 2007, a total of 1649 patients underwent primary PCI for STEMI at four New York State hospitals. Baseline clinical and angiographic characteristics and in-hospital outcomes were prospectively collected as part of the New York State PCI Reporting System (PCIRS). Patients with prior surgical or percutaneous coronary revascularization were compared to those without prior coronary revascularization. Of the 1649 patients presenting with STEMI, a total of 93 (5.6%) had prior CABG, 258 (15.7%) had prior PCI, and 1298 (78.7%) had no history of prior coronary revascularization. Patients with prior CABG were significantly older and had higher rates of peripheral vascular disease, diabetes mellitus, congestive heart failure, and prior stroke. Additionally, compared with those patients with a history of prior PCI as well as those without prior coronary revascularization, patients with previous CABG had more left main interventions (24% vs 2% and 2%; P<.001), but were less often treated with drug-eluting stents (47% vs 61% and 72%; P<.001).

Despite a low incidence of adverse in-hospital events, prior CABG was associated with higher all-cause in-hospital mortality (6.5% vs 2.2%; P=.012), and as a result, higher overall MACE (6.5% vs 2.7%; P=.039). By multivariate analysis, prior CABG (odds ratio, 3.40; 95% confidence interval, 1.15-10.00) was independently associated with in-hospital mortality. In contrast, patients with prior PCI had similar rates of MACE (4.3% vs 2.7%; P=.18) and inhospital mortality (3.1% vs 2.2%; P=.4) when compared to the de novo population. Patients with a prior history of CABG, but not prior PCI, undergoing primary PCI in the setting of STEMI have significantly worse in-hospital outcomes when compared with patients who had no prior history of coronary artery revascularization. Thus, only prior surgical — and not percutaneous — revascularization should be considered a significant risk factor in the setting of primary PCI.

Between 2004 and 2007, a total of 25,025 patients underwent PCI at these medical institutions, and their data were prospectively collected and submitted as required by the New York State Department of Health. Of these patients, a total of 1649 underwent primary PCI in the setting of an STEMI and constituted our study population. In this group, a total

differences in baseline clinical and procedural characteristics were noted among these groups (Table 1).

Discussion

While STEMI patients with prior CABG are well known to have worse clinical outcomes than those without prior revascularization, a direct comparison between patients who underwent primary PCI in the setting of prior CABG or prior PCI has not yet been reported. The principal findings from the present analysis suggest that in a contemporary, unrestricted patient population presenting with STEMI and undergoing primary PCI, patients with a prior history of CABG are:

(2) are more likely to undergo intervention on a native vessel and not a bypass graft;

(3) are more likely to be treated with bare-metal stents; and (4) have higher rates of in-hospital mortality without a significant increase in stroke or MI rates, when compared with patients with a prior history of PCI or patients with no previous history of coronary artery revascularization. Interestingly, these outcomes did not apply to patients with a history of prior PCI in this analysis. Instead, this cohort of patients had no significant difference in the rate of death, stroke, or periprocedural infarction when compared to a STEMI population without prior coronary revascularization, despite a significantly higher burden of comorbidities than those with no prior revascularization.

Our findings concur with previous studies that have shown higher mortality rates among patients with prior surgical bypass presenting with acute MI.7,9,14 Despite changes in revascularization strategies over the past 30 years, invasive therapies to treat acute coronary syndromes in patients with prior bypass surgery appear to have yielded less robust results than in other populations. In fact, Stone and colleagues already described in the Primary Angioplasty in Myocardial Infarction (PAMI-2) study that patients with a previous CABG undergoing primary PCI in the setting of an acute MI had significantly greater in-hospital mortality than patients without previous CABG, especially if the infarct-related vessel was a bypass conduit. However, by logistic regression analysis, only advanced age (P=.004), triple-vessel disease (P=.004), and Killip class ≥2 (P=.02) were independent predictors of in-hospital mortality in that study.13 In a more contemporary study of 128 STEMI patients with prior CABG, who were enrolled in the Assessment of PEXelizumab in Acute

STEMI and Prior Revascularization Myocardial Infarction (APEX-AMI) trial, Welsh and colleagues reported that post-CABG patients are less likely to undergo acute reperfusion (only 79% underwent primary PCI), have worse angiographic outcomes following primary PCI, and have higher 90-day mortality rates (19.0% vs 5.7%; P=.05). This difference was even more apparent when the infarct-related artery was a bypass graft that was not successfully reperfused (23.1% vs 8.5%; P=.03).3 These results are similar to our current analysis, where in-hospital mortality rates for patients who underwent primary PCI of a graft were numerically roughly 4 times as high as those undergoing PCI of a native vessel. Likewise, Gurfinkel et al reported a significant reduction in hard endpoints, such as all-cause death and MI at 6 months in patients treated with an invasive approach in the Global Registry of Acute Coronary Events (GRACE).15 In this large, multinational, observational study of 3853 patients with prior bypass surgery presenting with an acute coronary syndrome, only 497 (12.9%) were managed invasively and the rest were treated medically.

Despite significant differences in baseline characteristics, including a higher rate of STEMI in patients treated invasively (14% vs 27%; P<.001), in-hospital mortality was similar in both groups (3.4% vs 3.2%; P=.86). However, at 6-month follow-up, mortality was significantly higher in those patients treated medically (6.5% vs 3.4%; P<.02) as was the combined endpoint of death or MI (11% vs 5.8%; P<.01).

Whether these results apply to patients with a prior history of PCI has not been well defined. By the nature of vascular disease, patients with prior PCI are more likely to have more comorbidities than those without prior revascularization, a finding confirmed in our study. Despite considerable differences in baseline characteristics, however, these differences did not translate into a differential risk after STEMI. In fact, the cohort of patients presenting with STEMI who had a history of prior PCI had no statistically significant difference in in-hospital mortality or overall MACCE when compared to a population of patients presenting with STEMI in the absence of any prior revascularization.

Study limitations. The database utilized was derived from four New York State teaching hospitals and was designed to track quality of care and clinical outcomes. As all studies involving multicenter databases and registries, there is potential error in data entry and availability. Potential confounding comorbidities, including smoking status and family history of coronary artery disease, were not collected in this database, and information regarding long-term follow-up is not available, all of which are important limitations of this analysis. As such, deficiencies such as these limit the conclusions that can be drawn from our multivariate analysis. Additionally, there is no audit of data quality, and the low overall event rates limit effective statistical comparison.

Conclusions

In a contemporary cohort of STEMI patients undergoing primary PCI, a history of prior CABG was found to be an independent predictor of in-hospital mortality. In contrast, despite more comorbidities at the time of STEMI, patients with prior PCI had no significant difference in the rates of death, stroke, or periprocedural MI when compared to a STEMI population without prior coronary revascularization. Thus, only prior surgical — and not percutaneous — revascularization should be considered a significant risk factor in the setting of primary PCI.

Maddux PT et al. – The purpose of this study is to determine whether coronary artery anomalies can be detected on noncontrast computed tomography (CT) coronary artery calcium scoring (CCS) studies. Benign and malignant coronary artery anomalies can be detected with relatively high accuracy on noncontrast–enhanced CCS studies. CCS studies should be reviewed for signs of coronary artery anomalies in order to identify malignant variants with possible impact on patient management.

Based on noncontrast CCS studies, R1 and R2 correctly identified the left main origin in 123/126 (97.6%) and 121/126 (96%) patients; the left anterior descending origin in 125/126 (99.2%) and 122/126 (96.8%); the circumflex origin in 120/126 (95.2%) and 105/126 (83.3%); and the right coronary artery origin in 117/126 (92.9%) and 103/126 (81.7%), respectively.

Advanced CT reconstruction improves cardiac plaque assessment

April 12, 2013 — Automated plaque assessment in coronary CT angiography (CCTA) is a promising new way to evaluate a patient’s plaque burden quickly and noninvasively — but it won’t be quick or accurate without the use of advanced iterative reconstruction, according to researchers from Massachusetts General Hospital in Boston.

Automated techniques are still in their infancy, but once they become more reliable they promise to greatly improve risk assessment and management compared with, for example, calcium scoring, by precisely quantifying the amount of coronary artery plaque — fibrotic, lipid core, and calcium — that is present.

“We know the plaque volume and characteristics … are at least as important as the presence of calcium,” said Dr. Stefan Puchner in an interview with AuntMinnie.com. “If we could make plaque assessment more accurate, we could implement all this stuff in our daily practice.”

The process isn’t accurate today. Automated plaque quantification requires significant time for radiologists to fix the incorrectly drawn vessel wall boundaries, making it impractical for routine use. Manually drawing the boundaries would actually take about a day’s work for each patient, so automation is the only way forward, Puchner said. The group wanted to determine if an advanced reconstruction algorithm might produce fewer errors and make semiautomated plaque estimation practical.

In a study that reconstructed ex vivo coronary vessel segments using three different reconstruction methods, the study team found that, indeed, accuracy in plaque quantification depended on the reconstruction algorithm, as well as vessel size and the extent of calcifications. Using advanced reconstruction, fewer corrections were needed to the vessel wall segmentation, Puchner reported at the 2013 European Congress of Radiology (ECR) in Vienna. Specifically, they compared the use of automated vessel assessment using model-based iterative reconstruction (MBIR, GE Healthcare) compared with an earlier IR algorithm, advanced statistical iterative reconstruction (ASIR, GE), or conventional filtered back projection (FBP) reconstruction.

Cross section of a noncalcified plaque reconstructed with the three different algorithms (left to right: FBP, ASIR, MBIR). No significant differences can be seen between the three algorithms in terms of correct delineation of the plaque borders. All images courtesy of Dr. Stephan Puchner.

For subjects, the group examined three ex vivo human hearts imaged with CCTA and reconstructed with FBP, ASIR, and MBIR. An automated plaque quantification tool (Vitrea Cardiac Solutions, Vital) was applied to each of the three reconstruction algorithms to fit the outer and inner vessel wall boundaries in nine “triplets” constituting 27 vessels. Only the first 40 mm of the contrast-filled vessels was used for analysis.

Each coronary cross section for which the software assigned incorrect boundaries was tallied and corrected in a blinded manner. The group then compared the number of vessel wall corrections between the different reconstruction algorithms using a Chi-square test.

Cross ection of a calcified plaque reconstructed with the three different algorithms (left to right: FBP, ASIR, MBIR). In this case, FBP shows an incorrect delineation of the inner vessel wall boundary, including parts of the calcified plaque. In contrast, the vessel wall boundaries in the cross sections reconstructed with ASIR and MBIR are correctly delineated by the software.

“Our analysis included the percentage of corrections between the three algorithms, and a per-vessel comparison of the percentage of corrections between the three algorithms,” Puchner said in his presentation.

Cross section of a calcified plaque reconstructed with the three different algorithms (left to right: FBPR, ASIR, MBIR). In this case, FBP and ASIR show an incorrect delineation of the inner vessel wall boundary, including the whole or parts of the calcified plaque. Only in the cross section reconstructed with MBIR are the boundaries correctly delineated by the software.

The percentage of corrected cross sections was lower for MBIR (24.1%) versus ASIR (32.4%, p = 0.0003) and FBP (36.6%, p < 0.0001) — but the differences were only marginal between ASIR and FBP, he said.

“We found that MBIR works much better than the conventional algorithms … significantly reducing the number of corrections needed compared to FBP and ASIR, whereas the difference between the two other algorithms was not significant,”Puchner said.

The use of MBIR significantly reduced the need for vessel wall boundary corrections compared with other reconstruction algorithms, particularly at the site of calcifications.

Automated segmentation is certainly faster than manual processing, Puchner said. Just on the three cases used in the study and in the analysis of the proximal 40 mm of each vessel, use of the software saved about three hours compared with what manual segmentation would have required. There is significant processing time required to create MBIR reconstructions, he acknowledged, but in those cases, it’s the technologists, not the physicians, who are spending the additional time, he said.

“The next step will be to look at it in an in vivo environment, to see this application in a beating heart,”Puchner told AuntMinnie.com. And to test other applications and other iterative reconstruction schemes, of course.

“I’m pretty sure that the other newer algorithms will have similar effects, because overall some studies have shown that the use of newer algorithms reduces blooming effects and other stuff that makes it difficult for the software to delineate it correctly,” he said. With manual segmentation, radiologists tend to overcorrect for older reconstruction algorithms and undercorrect for newer techniques, “but if the software does it, the software is much more dependent on image quality, and it makes a difference if it was reconstructed with the newer algorithms or the older algorithms.”

Automated plaque measurements will also have to be compared with assessments in other modalities such as intravascular ultrasound, and even to histology using the donor hearts, he said.

It is well known that taking a good history and physical, getting a non-ischemic EKG, and serial cardiac biomarkers, results in a risk of death/AMI of <5% in 30 days. Patients, in whom you still suspect have CAD, should undergo provocative testing within the next 72 hours based on the AHA/ACC guidelines. Their guidelines deem provocative testing as including:

Exercise treadmill stress test,

Myocardial perfusion scan,

Stress echocardiography, and/or

Coronary CT angiography (CCTA).

Myocardial perfusion scans and stress echos have a sensitivity of 85–90% and specificity of 75–80%. In contrast, CCTA’s have been shown to have a sensitivity of 93-97% and specificity of 80-90%.

Recently two landmark trials were published in NEJM discussing the use of CCTA in the emergency department.

Cost was similar between two groups $4,289 CCTA vs $4,060 in Standard arm

Conclusion: CCTA decreases length of stay without an increase in rate of cardiovascular events.

Some discussion points worth mentioning:

CCTA with 0 lesions is NEGATIVE: These patients can certainly be discharged home with primary care follow up with a nearly 100% NPV for ACS/AMI.

CCTA with <50% lesion is NOT NEGATIVE: This patient has CAD. It may not be clinically significant, but we can see plaques. 2/3 of AMIs occur from plaques that have <50% stenosis. Certainly we can start risk factor modification with beta blockers, ASA, and statins, but there are no studies looking at how this group of patients will do long term.

CCTAs are anatomic studies and not functional studies. Identified lesions will lead to more diagnostic tests, which is one of the big arguments against CCTA. CCTA identifies CAD more often than standard stress modalities, which leads to more heart catheterizations and PCIs.

As the number of CT slice increases, radiation dose decreases:

A 64 slice CT = 10 – 15 mSv of radiation

A 128 slice CT = 5 – 10 mSv of radiation

A 256 slice CT = 1 – 5 mSv of radiation

In contrast, a single-view CXR = 0.02 mSV of radiation

There is currently an ongoing National Heart, Lung, and Blood Institute-funded trial called the PROMISE (Prospective Multi-center Imaging Study for Evaluation of Chest Pain) Study with 10,000 patients. Patients with symptoms suggestive of CAD will be randomized to a CCTA vs usual care with a functional test. What’s interesting about this study is it is being performed in the offices of primary care physicians and cardiologists rather than EDs. The study authors hypothesize that medically optimizing patients identified, as having non-obstructive CAD will yield improved long-term outcomes.

It is well known that in low risk patients, doing a good H&P, having a negative EKG (no ischemic changes), and negative serial cardiac biomarkers gives us about 99% NPV & 99% sensitivity for ACS/AMI. This is even without additional testing, such as CCTAs.So are CCTAs worth the cost and potential harms in this low-risk group to add another 1% to the 99% NPV and 99% sensitivity rates? In my opinion, that answer is NO.